Monique Elmaleh

Prenatal isolated mild ventriculomegaly: outcome in 167 cases

Objectiveu2002 To define the contribution of prenatal investigation and evaluate the prognosis of isolated mild ventriculomegaly (IMV).

Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations

Objective: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations. Methods: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family. Results: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1). Conclusions: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.

New spastic paraplegia phenotype associated to mutation of NFU1

Recently an early onset lethal encephalopathy has been described in relation to mutations of NFU1, one of the genes involved in iron-sulfur cluster metabolism. We report a new NFU1 mutated patient presenting with a milder phenotype characterized by a later onset, a slowly progressive spastic paraparesis with relapsing-remitting episodes, mild cognitive impairment and a long survival. The early white matter abnormalities observed on MRI was combined with a mixed sensory-motor neuropathy in the third decade. Our case clearly suggests the importance of considering NFU1 mutation in slowly evolving leukoencephalopathy with high glycine concentration.

TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients

BACKGROUNDnHypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases.nnnPATIENTS AND METHODSnThe study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood.nnnRESULTSnThe series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745Gxa0>xa0A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients.nnnCONCLUSIONSnTUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.

11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures.

Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2‐25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro‐rearrangements (n=188), the patient had an increased volume of the sub‐cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2‐25 deletion on brain anatomy.

Insertion of an extra copy of Xq22.2 into 1p36 results in functional duplication of the PLP1 gene in a girl with classical Pelizaeus-Merzbacher disease

BackgroundPelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder characterized by nystagmus, hypotonia, ataxia, progressive spasticity, and cognitive decline. PMD classically results from a duplication of a genomic segment encompassing the entire PLP1 gene. Since the PLP1 gene is located in Xq22, PMD affects mostly boys.Methods and resultsHere we report the case of a girl with typical PMD. Copy number analysis of the PLP1 locus revealed a duplication of the entire gene and FISH analysis showed that the extra copy of the PLP1 gene was actually inserted in chromosome 1p36. This insertion of an additional copy of PLP1 in an autosome led to a functional duplication irrespective of the X-inactivation pattern. Subsequent overexpression of PLP1 was the cause of the PMD phenotype observed in this girl. Further sequencing of the breakpoint junction revealed a microhomology and thus suggested a replication based mechanism (such as FoSTeS or MMBIR).ConclusionThis case emphasizes the susceptibility of the PLP1 locus to complex rearrangement likely driven by the Xq22 local genomic architecture. In addition, careful consideration should be given to girls with classical PMD clinical features since they usually experience complex PLP1 genomic alteration with a distinct risk of inheritance.

Heterozygous FA2H mutations in autism spectrum disorders.

BackgroundWidespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD.MethodsWe searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells.ResultsOne heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.ConclusionsWhile our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

PP12.10 – 2930: Expansion of the spectrum of TUBB4A mutations-related phenotype in hypomyelinating leukodystophy with atrophy of basal ganglia and cerebellum

Objective Hypomyelinating leukodystophy (HDL) with atrophy of basal ganglia (BG) and cerebellum (H-ABC or HDL6) has recently been associated with de Novo mutations of tubulin beta 4 (TUBB4A), a gene known to be involved in a dominant form of dystonia (DYT4). We propose to illustrate the large clinicoradiological spectrum of TUBB4A-gene-related mutations. Methods We report on 4 patients. Results Patient 1 presented with a classic form: nytagmus at 3 months of age, no head control; spastic tetraparesis, choreo-athetosic movements and axial dystonia were obvious before the age of 2 years. MRI showed hypomyelination with progressive BG atrophy. Patient 2 and 3 presented with predominant motor dysfunction which manifested as delayed acquisition of milestones and progressive severe spastic quadriplegia. Communication and receptive language were relatively preserved. Extrapyramidal symptomatology and cognitive dysfunction appeared after several years of evolution. MRI dysplayed hypomyelination, corpus callosum and cerebellar atrophy in patients 2 and 3, associated with cortical and BG atrophy in patient 3. Patient 4 acquired independent but unsteady walking at 12 months of age. He could run and read. He was explored for the first time at around 2 years for nystagmus and delayed acquisition of language. Motor functions deteriorated after a limb fracture (7y) in a context of very slowly progressive cerebellar syndrome, which had been evident at 3 years of age. Independent ambulation was lost at 8. MRI at 10 years showed hypomyelination and a slight atrophy of the striatum. All patients have diferent de Novo TUBB4A mutations. 2 are known, 2 are reported for the first time (patients 2, 4). Conclusion These observations illustrate a phenotypic continuum linked to TUBB4A mutations, as reported in the others HDL. This diagnosis should be discussed when HDL is associated with BG and/or cerebellum atrophy in a patient presenting with spasticity and/or progressive cerebellar symptoms.

Prenatal isolated mild ventriculomegaly : Outcome in 167 cases

OBJECTIVEnTo define the contribution of prenatal investigation and evaluate the prognosis of isolated mild ventriculomegaly (IMV).nnnDESIGNnRetrospective study.nnnSETTINGnUniversity hospital between January 1992 and December 2002.nnnPOPULATIONnOne hundred and sixty-seven cases of prenatal unilateral or bilateral IMV without any associated anomaly at the time of initial diagnosis.nnnMETHODSnComplementary investigations were performed: amniocentesis with karyotyping, screening for viruses and acetylcholinesterase electrophoresis, magnetic resonance imaging (MRI), and ultrasonography every 3-4 weeks.nnnMAIN OUTCOME MEASURESnResults of prenatal investigations, pregnancy outcome, and postnatal psychomotor development.nnnRESULTSnIMV was diagnosed around 26.5 weeks. Amniocentesis revealed four chromosomal anomalies and two cytomegalovirus infections. MRI diagnosed brain-associated anomalies in 15 cases and ultrasonographic monitoring highlighted malformations not initially diagnosed in 28 cases. Termination of pregnancy (TOP) was considered in 21 pregnancies (12.6%). Indications were aneuploidy, fetal infectious disease or associated malformations. In women for whom a TOP was considered, consanguinity, fetus of female sex and frontal horn enlargement were statistically more frequent, ventriculomegaly was more often bilateral and asymmetrical, atrial width, and the rate of progressive ventricular enlargement were significantly higher. One hundred and one children with prenatal IMV were assessed between 19 and 127 months (mean age 54.68 +/- 2.87 months). Twelve children had neurological disease or psychomotor delay and 89 children had a normal psychomotor development. Poor neurological outcome was more often associated with atrial width greater than or equal to 12 mm, asymmetrical bilateral enlargement, and progression of the ventriculomegaly.nnnCONCLUSIONnThe detection of IMV raises the question of the childs psychomotor development and justifies meticulous prenatal investigation. In addition to associated anomalies, three criteria are often associated with an unfavourable outcome: atrial width greater than 12 mm, progression of the enlargement, and asymmetrical and bilateral ventriculomegaly.